rs201477273

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4_StrongBS1_Supporting

The NM_002693.3(POLG):​c.2890C>T​(p.Arg964Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,613,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

11
5
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:9B:1

Conservation

PhyloP100: 7.27
Variant links:
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.028860092).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000433 (66/152276) while in subpopulation EAS AF= 0.0108 (56/5174). AF 95% confidence interval is 0.00856. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 NP_001119603.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 1 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
AF:
0.000434
AC:
66
AN:
152158
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0108
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000685
AC:
172
AN:
251154
Hom.:
1
AF XY:
0.000575
AC XY:
78
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00881
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000223
AC:
326
AN:
1461630
Hom.:
0
Cov.:
34
AF XY:
0.000198
AC XY:
144
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00599
Gnomad4 SAS exome
AF:
0.000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
AF:
0.000433
AC:
66
AN:
152276
Hom.:
1
Cov.:
33
AF XY:
0.000510
AC XY:
38
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0108
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000414
Hom.:
1
Bravo
AF:
0.000366
ExAC
AF:
0.000708
AC:
86
Asia WGS
AF:
0.00549
AC:
19
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 09, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 13, 2024Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365) -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsApr 30, 2024Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. (PMID: 17436221, 19364868, 19887119, 20176107, 25462018, 27987238, 25852747, 37470284) This variant segregates with disease in multiple families. -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 22, 2023BS1, PP3, PM3, PS3 -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 24, 2022- -
Progressive sclerosing poliodystrophy Pathogenic:1Uncertain:1Benign:1
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 01, 2018The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2025- -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 11, 2023- -
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:2
Likely pathogenic, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM3_VeryStrong+PP4+PS3+BS1 -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 14, 2024- -
not specified Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMar 30, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 28, 2024Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 27, 2024Criteria applied: PM3_VSTR,PS3_MOD,PP3 -
Hereditary spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenDec 01, 2017- -
MELAS syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPediatric Department, Xiangya Hospital, Central South University-This variant was observed in compound heterozygosity with variant (c.2584G>A) -
Mitochondrial DNA depletion syndrome 4b Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testing3billion, Medical GeneticsJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Spinocerebellar atrophy Pathogenic:1
Pathogenic, no assertion criteria providedprovider interpretationCodex Genetics LimitedFeb 28, 2019- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 01, 2024The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia. -
POLG-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 10, 2024The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;D
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
.;D
MetaRNN
Benign
0.029
T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.90
MVP
0.92
MPC
0.77
ClinPred
0.14
T
GERP RS
5.2
Varity_R
0.64
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201477273; hg19: chr15-89864088; COSMIC: COSV51521275; COSMIC: COSV51521275; API